Gallbladder and Sphincter of Oddi Disorders

Gastroenterology 2016;150:1420–1429
Gallbladder and Sphincter of Oddi Disorders
Peter B. Cotton,1 Grace H. Elta,2 C. Ross Carter,3 Pankaj Jay Pasricha,4
Enrico S. Corazziari5
1
Medical University of South Carolina, Charleston, South Carolina; 2University of Michigan, Ann Arbor, Michigan; 3Glasgow
Royal Infirmary, Glasgow, Scotland; 4Johns Hopkins School of Medicine, Baltimore, Maryland; and 5Universita La Sapienza,
Rome, Italy
GALLBLADDER AND SOD
The concept that motor disorders of the gallbladder, cystic
duct, and sphincter of Oddi can cause painful syndromes is
attractive and popular, at least in the United States. However, the results of commonly performed ablative treatments (eg, cholecystectomy and sphincterotomy) are not
uniformly good. The predictive value of tests that are often
used to diagnose dysfunction (eg, dynamic gallbladder
scintigraphy and sphincter manometry) is controversial.
Evaluation and management of these patients is made
difficult by the fluctuating symptoms and the placebo effect
of invasive interventions. A recent stringent study has
shown that sphincterotomy is no better than sham treatment in patients with post-cholecystectomy pain and little
or no objective abnormalities on investigation, so that the
old concept of sphincter of Oddi dysfunction type III is discarded. Endoscopic retrograde cholangiopancreatography
approaches are no longer appropriate in that context. There
is a pressing need for similar prospective studies to provide
better guidance for clinicians dealing with these patients.
We need to clarify the indications for cholecystectomy in
patients with functional gallbladder disorder and the relevance of sphincter dysfunction in patients with some evidence for biliary obstruction (previously sphincter of Oddi
dysfunction type II, now called “functional biliary sphincter
disorder”) and with idiopathic acute recurrent pancreatitis.
E1. Diagnostic Criteria for Biliary Pain
Pain located in the epigastrium and/or right upper
quadrant and all of the following:
1. Builds up to a steady level and lasting 30 minutes
or longer
2. Occurring at different intervals (not daily)
3. Severe enough to interrupt daily activities or lead
to an emergency department visit
4. Not significantly (<20%) related to bowel
movements
5. Not significantly (<20%) relieved by postural
change or acid suppression
Supportive Criteria
The pain may be associated with:
1. Nausea and vomiting
2. Radiation to the back and/or right infrasubscapular region
3. Waking from sleep
Keywords: Cholecystectomy; Biliary Pain; Post-Cholecystectomy
Pain; Sphincter Manometry; Sphincterotomy; Idiopathic
Pancreatitis;
Endoscopic
Retrograde
Cholangiopan
creatography.
F
unctional disorders of the gallbladder (GB) and the
sphincter of Oddi (SO) are controversial topics. They
have gone by a variety of names, including acalculous biliary
pain, biliary dyskinesia, GB dysmotility, and SO (or ampullary) stenosis. This articles builds on the Rome III
consensus,1 recognizing that the evidence base is slim. This
articles does not cover the anatomy and physiology, which
are well described elsewhere.
Biliary Pain
The concept that disordered function of the GB and SO
can cause pain is based mainly on the fact that many
patients have biliary-type pain in the absence of recognized
organic causes, and that some apparently are cured by
removal of the GB or ablation of the sphincter.
This definition for biliary pain differs from Rome III only in
quantitating “not significantly” to mean <20%. We included
the Rome III criterion that pains should be “not daily” although
this is not evidence-based. Further studies are needed.
Functional Gallbladder Disorder
Definition
In conformity with the Rome consensus that defines
functional gastrointestinal disorders as symptom complexes
Abbreviations used in this paper: CCK-CS, cholecystokinin-stimulated
cholescintigraphy; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FGBD, functional gallbladder disorder; GB, gallbladder; GBEF, gallbladder ejection fraction; MRCP, magnetic
resonance cholangiopancreatography; SO, sphincter of Oddi; SOD,
sphincter of Oddi dysfunction.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2016.02.033
Gallbladder and Sphincter of Oddi Disorders 1421
not explained by a clearly identified mechanism or by a
structural alteration, we use the term functional gallbladder
disorder (FGBD) to describe patients with biliary pain and
an intact GB without stones or sludge.
E1a. Diagnostic Criteria for Functional Gallbladder
Disorder
1. Biliary pain
2. Absence of
pathology
gallstones
or
other
structural
Supportive Criteria
1. Low ejection fraction on gallbladder scintigraphy
2. Normal liver enzymes, conjugated bilirubin, and
amylase/lipase
Since the diagnosis is primarily one of exclusion, the
prevalence depends on the rigor of investigation. Ultrasonography is the usual primary investigation, but endoscopic
ultrasound (EUS) is more sensitive for detecting small
stones and biliary sludge, and can also detect small tumors,
and subtle changes of chronic pancreatitis.
The only change from Rome III is that normal liver and
pancreatic enzymes have been moved to the supportive
category. There can be other reasons for elevated liver enzymes, like fatty liver disease, that do not rule out GB
dysfunction. We have also added a low ejection fraction on
GB scintigraphy as supportive. It is not required for the
diagnosis, nor is it specific for the diagnosis when abnormal.2
Epidemiology
Biliary pain is a common clinical problem, and cholecystectomy is a frequent operation. The number and proportion
done for FGBD seems to be increasing in the United States,
where case series now list it as the indication for
cholecystectomy in 10%20% of adults2,3 and in 10%50%
Figure 1. Potential etiological pathways and clinical outcomes in patients
with “biliary dyskinesia”
of children.4 FGBD is rarely diagnosed outside the United
States.5
Pathophysiology
FGBD is often diagnosed by a low gallbladder ejection
fraction (GBEF) at cholecystokinin-stimulated cholescintigraphy (CCK-CS). Although the relationship between GBEF and
clinical outcome remains unclear, gallbladder dysmotility
may still play a role in the pathogenesis of symptoms, by
promoting gallbladder inflammation, which is commonly
found. Microlithiasis is associated with a delayed ejection
fraction on scintigraphy.6 Investigators have found multiple
defects in gallbladder contractility, including spontaneous
activity and abnormal responses to both CCK and neural
stimulation.7 A vicious cycle of stasis and inflammation exists
in the GB. Some patients may have intrinsic defects in
contractility, and subtle defects in bile composition may also
play a role. Studies have shown elevated sphincter of Oddi
(SO) pressures in patients with GB dyskinesia, but without
correlation between GBEF and SO pressure.8 GB dysfunction
may represent a more generalized dysmotility, as in irritable
bowel syndrome and chronic constipation, and perhaps
gastroparesis.9 Experimental evidence has implicated several
molecules that can link inflammation to motility, the most
important of which may be prostaglandin E2 (PGE2).10,11
Possible etiological mechanisms and outcomes in patients
with “biliary dyskinesia” are illustrated in Figure 1.
Clinical Evaluation
GB stones should be excluded by ultrasound scanning
(repeated if necessary), and complemented with EUS. Other
tests may be needed to rule out peptic ulcer disease, subtle
chronic pancreatitis, fatty liver disease, or musculoskeletal
syndromes. Esophageal manometry, gastric emptying tests,
and transit studies may be required if symptoms suggest
alternative dysfunctional syndromes. Further management
depends on the level of clinical suspicion. The diagnosis of
FGBD may be made by exclusion if the pains are typical and
GALLBLADDER AND SOD
May 2016
1422 Cotton et al
severe. A key issue is whether current methods for assessing GB muscular function are useful.
Assessment of Gallbladder Emptying
GALLBLADDER AND SOD
CCK-CS is a popular diagnostic test, but its value is
controversial. The test involves the intravenous administration of technetium 99m (Tc 99m)labeled hepatobiliary
iminodiacetic acid analogs. These compounds are readily
excreted into the biliary tract, and are concentrated in the
GB. The net activity-time curve for the GB is derived from
serial observations, and GB emptying is expressed as the
GBEF, which is the percentage change of net GB counts.12
An interdisciplinary panel proposed a standardized test
and emphasized that proper patient selection is a critical
step when considering whether to perform CCK-CS, because
delayed emptying is seen in many other conditions,
including asymptomatic individuals and patients with other
functional gastrointestinal disorders. The injection of CCK
can cause biliary-like pain, but using this observation to
determine patient-care decisions was discouraged by the
panel, because CCK also increases bowel motility, which can
cause symptoms. In some countries, CCK preparations have
not been approved for human use.
Other imaging methods. GB emptying can be
assessed with ultrasound scanning after CCK or fatty meal
stimulation, but these methods have not become popular.
Attempts are being made to study emptying patterns during
magnetic resonance cholangiopancreatography (MRCP)13
and computed tomography (CT) scanning14 with results
that appear to mimic those of cholescintigraphy.
Treatment of Functional Gallbladder Disorder
Symptoms suggestive of FGBD often resolve spontaneously,3 so that early intervention is unwarranted. Patients
may respond to reassurance and medical treatments such as
antispasmodics, neuromodulators, or ursodeoxycholic acid,
Gastroenterology Vol. 150, No. 6
although their value has not been evaluated formally. Cholecystectomy is considered when these methods fail, and
symptoms are severe. The reported results of surgery vary
widely.2,3,15 Many claim benefit in >80% of patients, but
most studies are of poor quality with several potential
biases; none have limited intervention to patients with
negative EUS exams. There has been only one small randomized trial, favoring cholecystectomy.16 Several authorities have called for more definitive studies.3,17
The predictive value of the CCK-CS test is in question.
Two systematic reviews have concluded that there is
insufficient evidence to recommend its use.18,19 The review
by DiBaise and Oleynikov19 found that 19 of 23 papers
suggested that the GBEF was useful in selecting patients for
cholecystectomy. However, cholecystectomy is claimed to
benefit most patients with “typical biliary” symptoms,
raising the question as to what additional utility is afforded
by CCK-CS.20 One study reported symptomatic relief after
cholecystectomy in 94% of patients with a low GBEF, but
also in 85% of those with a normal GBEF.19 The degree of
dysfunction (ie, GBEF <20% vs <35%) did not improve the
predictive value.21 Similarly, in a study of patients with
reduced GBEF (<35%), CCK-CS was of minimal clinical
utility in predicting symptomatic relief in patients with
atypical symptoms, 30% resolving spontaneously, and of
those with persistent symptoms, only 57% benefitted from
cholecystectomy.20 A “blind” cholecystectomy based on
symptoms without CCK-CS evidence has been reported with
a >90% satisfaction rate. That many patients with suspected FGBD are not helped by cholecystectomy is shown by
the significant number who present afterward with “postcholecystectomy pain,” and are considered for another
contentious diagnosis, sphincter of Oddi dysfunction (SOD).
Conclusion. Current evidence indicates that cholecystectomy can provide symptom relief in many patients with
acalculous biliary pain, and GBEF is often low in these patients. However, more stringent studies are needed to
Figure 2. Evaluation of
biliary pain in patients with
intact GB. In patients with
biliary pain and negative
investigations
(including
EUS), the decision to proceed to cholecystectomy
or dynamic imaging of the
gallbladder will depend on
the strength of the clinical
suspicion. CT, computed
tomography; EGD, esophagogastroduodenoscopy;
MRI, magnetic resonance
imaging; RUQ, right upper
quadrant; US, ultrasound.
establish which patients are likely to benefit (or not), and to
clarify the predictive value of the CCK-CS test.
One approach to managing these patients is shown in
Figure 2, but the need for more research is obvious.
Future Research. We need to know more about the
etiology of FGBD, better methods for making and excluding
the diagnosis, the natural history, and the role of different
treatments. More stringent prospective studies of cholecystectomy, with independent outcome assessments, are
required to provide a more evidence-based approach.
Functional Biliary Sphincter Disorder
Dysfunction of the biliary sphincter is commonly
considered in patients with biliary-type pains after cholecystectomy, when stones and other pathology are
excluded.1,22
Epidemiology
Many patients have persistent or recurrent pain after
cholecystectomy.23,24 The proportion is higher in patients
who have had elective rather than emergency surgery, in
patients without GB stones, and in those with less typical
symptoms.25
Diagnostic Criteria
The longstanding popular classification of 3 clinical
types of SOD1,22,26 seemed validated by the fact that the
likelihood of abnormal sphincter manometry, and relief by
sphincterotomy, appeared to correlate with the types.
However, most data came from cohort studies of poor
quality,27,28 and one showed no such correlation.29 Earlier
recommendations were that type I patients (with a dilated
bile duct and elevated liver enzymes) should undergo
biliary sphincterotomy without manometry, and that type II
(dilated duct or elevated liver enzymes) patients and type
III (no abnormalities) patients should be considered for
manometry-directed sphincterotomy.1
This classification is now outdated and should be
abandoned. Most patients with prior SOD type I have
organic stenosis rather than functional pathology; they
benefit from biliary sphincterotomy. The EPISOD (Evaluating Predictors and Interventions in Sphincter of Oddi
Dysfunction) trial30 showed that patients with SOD type III
do not respond to sphincter ablation better than sham
intervention. We therefore now recommend using the term
suspected functional biliary sphincter disorder (suspected
FBSD) for patients with post-cholecystectomy pain and
some objective findings (the prior SOD type II). Further
research is needed to establish more precisely which clinical
features and investigations can best identify those who are
likely to respond (or not) to sphincter treatments.
E1b. Diagnostic Criteria for Functional Biliary Sphincter
of Oddi Disorder
1. Criteria for biliary pain
2. Elevated liver enzymes or dilated bile duct, but
not both
Gallbladder and Sphincter of Oddi Disorders 1423
3. Absence of bile duct stones or other structural
abnormalities
Supportive Criteria
1. Normal amylase/lipase
2. Abnormal sphincter of Oddi manometry
3. Hepatobiliary scintigraphy
Changes Since Rome III. Elevated liver enzymes or a
dilated bile duct (but not both) are now required, rather
than supportive, criteria. Normal amylase and/or lipase
have been moved to supportive criteria because they may
occur in some episodes of pain. We have added abnormal
biliary manometry as supportive because randomized trials
showed that it is predictive of response to biliary sphincterotomy.31,32 Hepatobiliary scintigraphy is also included,
although its value is disputed.
Pathophysiology
Classical teaching is that aberrant sphincter physiology
leads to biliary pain by increased resistance to bile outflow
and subsequent rise in intrabiliary pressure. This concept is
intuitively appealing, leading to widespread acceptance,
especially by biliary endoscopists. However, both theoretical
and experimental evidence indicate a more complex
pathophysiology.
There is evidence that sphincter dynamics are altered
after cholecystectomy.33 Animal studies have shown a
cholecystosphincteric reflex with distention of the GB that
results in sphincter relaxation.34 Interruption of this reflex
could affect sphincter behavior by an altered response to
CCK, or because the loss of innervation unmasks the direct
contractile effects of CCK on smooth muscle. Abnormalities
in both basal pressure and responsiveness to CCK have also
been described in humans.35
The simple concept of SOD leading to obstruction and
biliary pain is now being challenged, as the EPISOD trial has
shown.30 One explanation for this syndrome stems from the
concept of nociceptive sensitization.36 Significant tissue
inflammation, such as cholecystitis, will activate nociceptive
neurons acutely and, if it persists, will also result in sensitization and the gain in the entire pain pathway is increased.
In most patients with GB disease, cholecystectomy removes
the ongoing stimulus and the system reverts back to its
normal state. However, in a subset of patients, the “gain”
stays at a high level (Figure 1). In such patients, even minor
increases in biliary pressure (within the physiological
range) can trigger nociceptive activity and the sensation of
pain (allodynia).
A relevant related phenomenon is cross-sensitization.
Many viscera share sensory innervation. For example,
nearly half of the sensory neurons in the pancreas also
innervate the duodenum.37 Therefore, it is difficult to
distinguish pain resulting in one organ from that in another.
Persistent sensitization in one organ can lead to
GALLBLADDER AND SOD
May 2016
1424 Cotton et al
sensitization of the nociceptive pathway from an adjacent
organ. Thus, an entire region can be sensitized with innocous stimuli (such as duodenal contraction after a meal)
leading to pain that was indistinguishable from that associated with the initial insult. Evidence for this was provided
by a study in which patients with post-cholecystectomy pain
were found to found to have duodenal, but not rectal,
hyperalgesia.38 A strong case can be made for nociceptive
sensitization to be the principal cause of pain. Motor phenomena, such as sphincter hypertension, might still be
relevant, but more as a marker for the syndrome rather than
the cause.
Exclusion of Organic Disease
GALLBLADDER AND SOD
The first task in patients with post-cholecystectomy pain
is to exclude organic causes. Possibilities include retained
stones or partial GB; postoperative complications (such as a
bile leak or duct stricture); other intra-abdominal disorders,
such as pancreatitis, fatty liver disease, peptic ulceration,
functional dyspepsia and irritable bowel syndrome;
musculoskeletal disorders; and other rare conditions. Nonbiliary findings are more likely when the symptoms are
atypical and longstanding, similar to those suffered preoperatively and without a period of relief postoperatively, and
when the GB did not contain stones.1,25,39
The initial diagnostic approach should consist of a
careful history and physical examination, followed by standard liver and pancreas blood tests, upper endoscopy, and
abdominal imaging. Although ultrasound or computed tomography scanning may be used initially, MRCP or EUS
provide more complete information. The report of a “dilated
bile duct” on any of these studies is difficult to interpret. It is
widely believed that the bile duct enlarges after cholecystectomy. However, some studies have shown no change,
others only a slight increase in size; there is a gradual increase with age.40–43 Regular narcotic use can cause biliary
dilation, although usually associated with normal liver enzymes.44 EUS is the best way to rule out duct stones and
pathology of the papilla.45,46
Noninvasive Testing
A major problem with assessing diagnostic tools in this
context is the lack of a gold standard. One could argue that
the only proof that the sphincter is (or was) the cause of the
pain is if patients are satisfied by the results of sphincter
ablation, albeit recognizing the often prolonged placebo effect of endoscopic retrograde cholangiopancreatography
(ERCP) intervention.30 There are very few studies with
objective blinded assessments and even fewer randomized
trials. Many tests are assessed by comparison with the results of manometry, whose validity is also uncertain. Thus,
arguments are often circular, and our comments on the
value of these various tests are not based on solid evidence.
Liver enzymes, which peak with attacks of pain, might be a
good sign of obstruction by spasm (or passage of stones),47
but confirmation is lacking. Another problem is that most
patients have intermittent pains, so that measurements
taken when pain-free are open to question.
Gastroenterology Vol. 150, No. 6
The drainage dynamics of the bile duct have been tested
after stimulation with a fatty meal or injection of CCK and
measuring any dilatation of the duct with abdominal or
endoscopic ultrasound. These techniques deserve further
evaluation, and there is potential for studying dynamic parameters with contrast agents during MRCP13 and
computed tomography scanning.14
Hepatobiliary scintigraphy. Hepatobiliary scintigraphy involves intravenous injection of a radionucleotide
and deriving time-activity curves for its excretion
throughout the hepatobiliary system. This technique has
been used to assess the rate of bile flow into the duodenum
and to look for any evidence of obstruction. Interpretation
of the literature is difficult due to the use of different test
protocols, diagnostic criteria, and categories of patients, and
whether the results are compared with manometry (usually) or the outcome of sphincterotomy. Various parameters
are used: time to peak activity, slope values, and hepatic
clearance at predefined time intervals, disappearance time
from the bile duct, duodenal appearance time, and the hepatic hilumduodenum transit time.48–51 One study in
asymptomatic post-cholecystectomy subjects showed significant false-positive findings and intra-observer variability.52 The reported specificity of hepatobiliary
scintigraphy was at least 90% when manometry was used
as the reference standard, but the level of sensitivity is more
variable.53 Although hepatobiliary scintigraphy with hepatic
hilumduodenum transit time was shown to be predictive
of the results of sphincterotomy in type I and II patients,54 it
is not widely used currently; further studies are needed.
Endoscopic retrograde cholangiopancreatography
and sphincter of Oddi manometry. ERCP should be
reserved for patients who need sphincter manometry or
endoscopic therapy, such as those with strong objective
evidence for biliary obstruction.
Manometry technique. ERCP allows measurement of
both the biliary and pancreatic sphincters, but the method is
imperfect. Recording periods are short and subject to
movement artifact. The effects of medications commonly
used for sedation and anesthesia have not been studied
sufficiently. Furthermore, reproducibility is in question.55
The assessable variables at SO manometry include the
basal sphincter pressure and the phasic wave amplitude,
duration, frequency, and propagation pattern. However,
only basal pressure has so far been shown to have clinical
significance.31,32 The standard upper limit of normal for
baseline biliary sphincter pressure is 3540 mm Hg.
Normal pancreatic sphincter pressures are accepted as
similar to those of the bile duct, although reference data are
more limited.
In normal volunteers, pressures obtained from the bile
duct and pancreatic duct are similar.56 However, abnormalities may be confined to one side of the sphincter in up
to 50% of patients.57–59 For patients in whom the indication
for SO manometry is biliary pain and not idiopathic
pancreatitis, some authorities avoid pancreatic cannulation
entirely to reduce the frequency of pancreatitis. The value of
studying the pancreatic sphincter has been questioned,
given 2 recent studies that failed to show superiority for
May 2016
Non-Manometric Endoscopic Retrograde
Cholangiopancreatography Diagnostic
Approaches
Trial placement of a pancreatic or biliary stent to predict
response to subsequent sphincterotomy has been proposed as
an alternative method for diagnosing SOD, but should be
avoided due to the very high risk of inducing pancreatitis.
Injection of Botulinum toxin has been shown to relax the
sphincter complex temporarily64,65 and no complications have
been reported. It is claimed to predict which patients would
benefit from sphincterotomy,65,66 but more data are needed.
Figure 3 suggests diagnostic pathways, based on current
limited evidence.
Figure
3. Postcholecystectomy
biliary
pain. Patients with clear
evidence
for
biliary
obstruction should have a
biliary sphincterotomy; if
the evidence is less
convincing, further testing
with manometry or scintigraphy may be helpful.
CT,
computed
tomography; HB is hepatobiliary; US, ultrasound.
Treatment
Current recommendations for management of patients
with suspected functional biliary sphincter disorder are
based on expert consensus, with inadequate evidence. Many
patients are disabled with pain and desperate for assistance.
The placebo effect of intervention is strong, with about onethird of sham-treated patients claiming long-term benefit in
blinded randomized studies.30,31,32,63
Medical therapy. Because of the risks and uncertainties involved in invasive approaches, it is important
to explore conservative management initially. Nifedipine,
phosphodiesterase type-5 inhibitors, trimebutine, hyoscine
butylbromide, octreotide, and nitric oxide have been shown
to reduce basal sphincter pressures in SOD and asymptomatic volunteers during acute manometry.67,68 H2 antagonists, gabexate mesilate, ulinastatin, and gastrokinetic
agents also showed inhibitory effects on sphincter motility.
Amitriptyline, as a neuromodulator, also has been used
along with simple analgesics. A trial of duloxetine had
encouraging results.69 A French group was able to avoid
sphincterotomy in 77% of patients with suspected SOD
using treatment with trimebutine and nitrates.70 None of
these drugs are specific to the SO and therefore may also
have positive effects in patients with nonbiliary dysfunctional syndromes. Transcutaneous electrical nerve stimulation71 and acupuncture72 also have been shown to reduce
SO pressures, but their long-term efficacy has not been
evaluated.
Endoscopic therapy: sphincterotomy. Consensus
opinion remains that patients with definite evidence for SO
obstruction (former biliary SOD type I) should be treated
with endoscopic sphincterotomy without manometry.1 The
GALLBLADDER AND SOD
dual sphincterotomy over biliary alone in suspected biliary
sphincter dysfunction and in idiopathic recurrent
pancreatitis.30,60
Solid-state manometry catheters have also been used,
with results identical to those of the water-perfused system.61 A technique using a sleeve device also showed
similar results, with the advantage of reducing movement
artifacts, but is not commercially available.62
Indications for manometry. Sphincter manometry
has been recommended in patients with suspected biliary
type II SOD because 3 randomized trials showed that biliary
manometry predicted the response to biliary sphincterotomy.31,32,63 However, in clinical practice, biliary sphincterotomy is often performed empirically in those patients.
Because of the EPISOD trial findings, manometry is no
longer recommended in patients without objective findings
(prior type III SOD).30
Gallbladder and Sphincter of Oddi Disorders 1425
1426 Cotton et al
Gastroenterology Vol. 150, No. 6
GALLBLADDER AND SOD
evidence base for biliary sphincterotomy in patients with
less objective clinical evidence (prior SOD type II) is not
strong; many studies have been retrospective, unblinded,
and have not used objective assessments.27,28 One large
study claimed success in about three-quarters of patients
simply because they did not return to the treatment site for
further intervention.73 The most convincing data come from
3 small randomized studies of suspected type II patients,
which showed that sphincterotomy was more effective than
a sham procedure in patients with elevated basal biliary
sphincter pressures.31,32,63 The EPISOD trial showed that
there is no justification to perform manometry or sphincterotomy in patients with normal labs and imaging (prior
SOD type III patients).30 Outcomes were also poor in a
parallel observational study (EPISOD 2) of 72 similar patients who did not agree to randomization and underwent
manometry-directed sphincterotomies (Table 1). ERCP in
this context is clinically dangerous and has medicolegal
consequences when complications arise.
Better predictors of outcomes of sphincterotomy in patients with “suspected functional biliary sphincter disorder”
(prior SOD II) are needed. Freeman and colleagues29
showed that normal pancreatic manometry, delayed
gastric emptying, daily opioid use, and age younger than 40
years predicted poor outcomes. It has been reported that
patients are more likely to respond if their pain was not
continuous, if it was accompanied by nausea and vomiting,
and if there had been a pain-free interval of at least 1 year
after cholecystectomy.74 Future studies should re-examine
these items and a range of possible predictors, including
laboratory findings (fluctuating or not), the actual size of the
bile duct, and whether it is known to have enlarged since
surgery, the severity and pattern of the pain, the presence of
other functional disorders, psychosocial factors, the reason
for the cholecystectomy and response to it, as well as any
potential diagnostic methods as described here.
Endoscopic retrograde cholangiopancreatography
adverse events. ERCP in patients with SOD (with or
without manometry) is associated with a high risk of
pancreatitis. The rate is 10%15%, even in expert hands
using pancreatic stent placement and/or rectal nonsteroidal
anti-inflammatory drugs.75,76 Sphincterotomy adds the risks
Table 1.Results of the EPISOD Randomized Trial and the
EPISOD 2 Observational Study
Study
EPISOD
EPISOD 2
Sphincter treatment
n
None (sham)
Any sphincterotomy
Biliary sphincterotomy without PSH
Biliary sphincterotomy with PSH
Dual sphincterotomy with PSH
Biliary sphincterotomy
Dual sphincterotomy
None
73
141
43
51
47
21
39
12
Pain relief,
n (%)
27
32
8
10
14
5
12
2
(37)
(23)
(19)
(20)
(30)
(24)
(31)
(17)
EPISOD, Evaluating Predictors and Interventions in Sphincter of
Oddi Dysfunction; PSH, pancreatic sphincter hypertension.
of bleeding and retroduodenal perforation, which both
occur in about 1% of cases, and also a significant risk for
late restenosis, especially after pancreatic sphincterotomy.
Surgical therapy. Surgical sphincteroplasty can be
performed primarily or after failed endoscopic therapy. Case
series and one small randomized study (published in abstract) suggest good outcomes in most patients,63,77–80 but
endoscopic intervention is currently preferred for primary
treatment.
Functional Biliary Sphincter Disorder in
Patients With an Intact Gallbladder
Very few studies have addressed the role of sphincter
dysfunction in patients with biliary-type pain in the presence
of the GB. Two small retrospective case series showed a lower
chance of clinical response to biliary sphincterotomy in patients with an intact GB than in those with prior cholecystectomy.81,82 Response was more likely if the bile duct was
dilated. A third study reported that 43% had long-term pain
relief.83 More information is needed on how to manage these
patients. At this time, it is not appropriate for patients with
intact GBs (without stones) to undergo ERCP, manometry, or
sphincterotomy unless they are enrolled in a clinical trial.
Summary of Functional Biliary Sphincter Disorder
Post-cholecystectomy pain is a common complaint, the
cause of which often remains obscure after standard investigations. This is a clinical minefield, which patients and
physicians should enter only with extreme caution, especially when considering the use of ERCP and sphincterotomy, with or without sphincter manometry. The EPISOD
trial again showed the strength of the placebo effect of
intervention, which bedevils the assessment of all types of
treatment. Further stringent trials are needed.
Functional Pancreatic Sphincter
Dysfunction
The idea that dysfunction of the pancreatic sphincter can
cause pancreatic pain and pancreatitis is popular. It seems a
logical extension to the consensus that sphincter hypertension can cause biliary pain. Obstruction at the sphincter
causes pancreatitis in animal experiments, and in several
clinical situations, including tumors of the papilla, duct
stones, and by mucus plugs in intrapancreatic mucinous
neoplasm. In addition, opiates increase sphincter pressure
and have been implicated in attacks of pancreatitis.84
Finally, patients with unexplained attacks of pancreatitis
are often found to have elevated pancreatic sphincter
pressures.28,85–87
Proof that elevated sphincter pressures actually cause
pancreatitis would require demonstration of abnormal
sphincter activity, and resolution of the attacks after
sphincter ablation. Earlier small cohort studies suggested
benefit after endoscopic or surgical sphincterotomy with
recurrence in less than one-third of patients.28 More recent
studies suggest that pancreatitis recurs in about 50% of
patients with longer follow-up.88,89 A recent prospective
May 2016
Can Pancreatic Sphincter Dysfunction
Cause Pain Without Pancreatitis?
Historically, it was proposed that SOD can cause
pancreatic pain without definite evidence of pancreatitis
and, indeed, a categorization of pancreatic SOD types similar
to that used in suspected biliary SOD was suggested.28
Pancreatic pressures higher than the accepted norm are
found in many patients with unexplained pain (including
those in the EPISOD study). Many such patients have undergone sphincterotomies, but proof of benefit is lacking.85
Diagnosis and Criteria for Functional
Pancreatic Sphincter Disorder
Given the uncertainty about the role of pancreatic SOD,
efforts to provide useful guides to investigation and treatment are currently speculative. Pancreatic SOD may be
considered in patients with documented acute recurrent
pancreatitis, after a comprehensive review of known etiologies and search for structural abnormalities, and with
elevated pancreatic pressures on manometry.
E2. Diagnostic Criteria for Pancreatic Sphincter
of Oddi DisorderAll of the following:
1. Documented recurrent episodes of pancreatitis
(typical pain with amylase or lipase >3 times
normal and/or imaging evidence of acute
pancreatitis)
2. Other etiologies of pancreatitis excluded
3. Negative endoscopic ultrasound
4. Abnormal sphincter manometry
Alternative diagnostic tests. Measuring the size of
the pancreatic duct by MRCP or EUS before and after an
intravenous injection of secretin has been used to demonstrate sphincter dysfunction. One report suggests that the
results do not correlate with sphincter manometry, but may
predict the outcome of sphincterotomy in patients with
otherwise unexplained pancreatitis.90 This test deserves
further assessment. Injection of Botulinum toxin into the
sphincter and temporary stenting have been used in this
context, but have not been validated.91
Treatment
Patients with recurrent acute pancreatitis that remains
unexplained after detailed investigation should be reassured
that the attacks may stop spontaneously and if they recur,
they usually follow the same course and are rarely life
threatening. They should be counseled to avoid factors that
may precipitate attacks (eg, alcohol, opiates). While certain
medications (such as antispasmodics and calcium channel
blockers) are known to relax the sphincter, there have been no
trials of their use.
In earlier days, cholecystectomy was often recommended after 2 unexplained attacks of pancreatitis,
assuming that small stones or microlithisasis were responsible.92 That approach seems less acceptable now that these
are easier to exclude with modern imaging. Others have
approached the problem of microlithiasis with biliary
sphincterotomy, or treatment with ursodeoxycholic acid,
but current data are unconvincing.
Pancreatic sphincterotomy would be the logical treatment
if the sphincter dysfunction is indeed causative. Historically,
complete division of the both sphincters was done by an open
transduodenal approach. Case series of patients who have
undergone this procedure have claimed resolution of episodic
pancreatitis in the majority of patients.93,94 The pancreatic
sphincterotomies performed endoscopically are much
smaller, and repeat manometry studies in patients with
recurrent problems often show them to be incomplete.60,89
Manometry has not been repeated in patients without
recurrent symptoms, so it is not clear whether treatment has
failed because of inadequacy of the sphincterotomy, or an
incorrect diagnosis. Stenosis of the pancreatic orifice is not
uncommon after pancreatic sphincterotomy, and repeat ERCP
treatment rarely resolves the problem. Endoscopic biliary
sphincterotomy is known to reduce pancreatic sphincter
pressures in many cases, and the recent prospective trial
showed no benefit of adding pancreatic sphincterotomy.60
At the present time, practitioners and patients should
approach invasive treatments in this context with considerable caution, recognizing the short and long-term risks,
and the marginal evidence for benefit. Additional stringent
trials are required.
Functional Pancreatic Sphincter Dysfunction
and Chronic Pancreatitis
Elevated pancreatic sphincter pressure has been
described in 50%87% of patients with chronic pancreatitis of many etiologies.94,95 Whether it plays a role in the
pathogenesis or progression of chronic pancreatitis is not
known. Endoscopic pancreatic sphincterotomy was reported to improve pain scores in short-term uncontrolled
studies in 60%65% of chronic pancreatitis patients with
pancreatic SOD,95 but long-term data are not available. The
role of endoscopic treatment (in the absence of stones or
strictures) remains unclear.
GALLBLADDER AND SOD
study showed a 50% recurrence rate in 2 years after
sphincterotomy in patients with raised pressures.60 This did
show a 3.5 times greater likelihood of recurrent attacks in
patients with elevated pressures without treatment. However, there was no additional benefit of dual (pancreatic and
biliary) sphincterotomy over biliary sphincterotomy alone.
Whether these reports mean that sphincterotomy is beneficial is difficult to interpret in the absence of controls.
It remains possible that the finding of sphincter abnormality in these patients is an epiphenomenon, the result of
previous attacks, or due to an unexplained cause. The fact
that many patients eventually develop features of chronic
pancreatitis suggests that the underlying pathogenesis of
the disease is not altered.
Gallbladder and Sphincter of Oddi Disorders 1427
1428 Cotton et al
Summary of Functional Pancreatic
Sphincter Dysfunction
There is no proven role for ERCP with manometry in patients with suspected pancreatic pain without evidence for
pancreatitis. Patients with a single episode of unexplained
acute pancreatitis should not undertake the risks of ERCP
because a second episode may never happen, or may be long
delayed. Similarly, there is currently no clear role for treating
SOD in patients with chronic pancreatitis. The optimal
approach for patients with unexplained recurrent acute
pancreatitis needs clarification by stringent studies with long
follow-up. Currently, it appears reasonable to consider ERCP
with sphincterotomy when manometry is abnormal. Biliary
sphincterotomy alone appears as effective as dual sphincterotomy, and likely lowers the short and long-term risks. Patients should understand the significant risks and uncertain
benefits.
GALLBLADDER AND SOD
Conclusions
Our understanding of functional gall bladder and
sphincter disorders is far from complete, and our current
treatment recommendations are not firmly evidence-based.
The need for more stringent prospective research is obvious.
Supplementary Material
Note: The first 50 references associated with this article are
available below in print. The remaining references accompanying this article are available online only with the electronic version of the article. Visit the online version of
Gastroenterology at www.gastrojournal.org, and at http://
dx.doi.org/10.1053/j.gastro.2016.02.033.
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Reprint requests
Address requests for reprints to: Peter B. Cotton, MD, FRCP, FRCS, Digestive
Disease Center, Medical University of South Carolina, 25 Courtenay Drive,
ART, Charleston, SC, 29425-2900. e-mail: [email protected]; fax: (843)
876-4718.
Conflicts of interest
The authors disclose no conflicts.
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